Despite advances in standard therapies,30-40% of patients with early-stage breast cancer will develop post- therapy metastases. Breast cancer stem cells (BCSC) give rise to metastases and are resistant to standard chemotherapy and radiation therapy. Moreover, radiation (IR) or chemotherapy (chemo) can reprogram nonstem breast cancer cells into BCSC, namely iBCSC. Thus, effective cancer treatment must eliminate therapy-resistant BCSC and block formation of therapy-induced BCSC. Both BCSC/iBCSC express elevated levels of aldehyde dehydrogenase (ALDH). Disulfiram (DSF) is an FDA-approved inhibitor of ALDH for treatment of alcoholism. Its toxicity to breast cancer cells is enhanced by the binding of the essential trace element copper (Cu) to form DSF/Cu complexes. DSF/Cu is an effective proteasome inhibitor resulting in inhibition of the key transcriptional factor NF-?B, which is linked to cancer and radio-, chemo-resistance and Consistent with the most recent epidemiological report indicating that DSF significantly reduced patient risk of death from cancer, we found that DSF and IR effectively targets BSCS/iBCSC and significantly prevented lung metastasis in the aggressive mouse mammary tumor 4T1 model, while IR alone was ineffective. We also found that DSF/Cu can block in vitro and in vivo IR- or chemo-induced BCSC via down- regulation of the NF-?B-stemness gene pathway and target BCSC by reduction of pro-survival ALDH activity and induction of endoplasmic reticulum (ER) stress- immunological cell death (ICD). Moreover, DSF and IR induced a robust immune response against primary tumor and lung metastasis in 4T1 mouse models. ICD cell stemness. These findings provide the rationale for our hypothesis that DSF/Cu, which induces of therapy-resistant BCSC and blocks formation of IR- or chemo- induced BCSC, is effective in preventing breast cancer metastasis when combined with the most frequently used standard treatment, i.e., surgery, IR and chemo. Since Cu is tumor promoting and found at elevated levels in tumors and sera of breast cancer patents, tailored use of exogenous Cu with DSF in vivo will be based on tumor Cu level in all Aims. In Aim1, we will assess the therapeutic efficacy of IR and/or chemo combined with DSF/Cu on preventing metastasis of patient breast cancer-derived xenograft (PDX) and MMTV-PyMT transgenic mammary tumors in an adjuvant setting. In Aim2, we will assess the therapeutic efficacy of chemo combined with DSF/Cu on preventing metastasis of PDX and MMTV-PyMT tumors in a neoadjuvant setting. In Aim3, we will analyze the mechanisms by which DSF/Cu systemically targets BCSC via induction of ICD and modulation of IR-induced immune response . At the conclusion of this study, we will have: i) evaluated DSF/Cu as a novel agent targeting BCSC/ iBCSC in the context of surgery, chemo-and/or IR treatment; ii) elucidated mechanisms by which DSF/Cu and IR induce a robust immune response against breast cancer metastasis; and iii) formed the preclinical foundation for designing a clinical research program to test this novel therapy to prevent post-therapy breast cancer metastasis.